The aims of the proposal are in accord with the mission of the Medications Development Division of NIDA to provide new treatments for substance abuse. The principal aim of the project is to provide potential treatment agents for opiate and polydrug dependence by targeting single chemical entities that mimic the profile produced by a buprenorphine/naltrexone combination. There is evidence from both clinical and preclinical research that this combination can help prevent relapse to drug taking behavior. The target compounds lack of mu opioid receptor efficacy will render the compounds safe and ethically acceptable for use in both opioid using and non-opioid using addicts. Efficacy as treatment agents will come from the compounds kappa opioid receptor antagonist activity, coupled with agonism at NOP (nociceptin) receptors. Lead compounds have been identified within the orvinol series, a series which has produced several compounds of clinical or veterinary utility, including buprenorphine. A number of lead compounds, previously evaluated in vitro, will be re-synthesized and further evaluated to confirm that they have the desired properties in vivo, including an extended duration of action. Mu and kappa opioid receptor efficacy, as well as NOP receptor affinity can be controlled through appropriate choice of C20 substituents in the orvinol series. Using molecular modeling we have established a structural relationship between these orvinols and related series of ligands that should allow the rationale design of further compounds possessing the desired pharmacological profile. These new series of ligands also access the region of space accessed by the C20 substituents in the orvinols. To evaluate newly synthesized compounds, assays have been chosen that will allow the desired profile to be identified in vitro, before then using behavioral assays with select compounds to determine their opioid activity in vivo and assess their ability to act as relapse prevention agents in a model of drug relapse. PUBLIC HEALTH RELEVANCE: Drug abuse and addiction, including polydrug abuse, continues to be a major problem in the United States and throughout the world. One of the main problems in drug abuse treatment is the high rate of relapse to drug taking. This research aims to provide improved treatment agents that can be used as relapse prevention agents. The target compounds will not have the side effects associated with current treatments for opioid abuse, such as abuse potential or respiratory depression and will therefore have an increased safety profile.